This application addresses broad Challenge Area (15): Translational Science, and Specific Challenge Topic 15-NS-104: Early Stage Therapy Development. We propose to develop and evaluate small-molecule orexin receptor agonists as preclinical leads for the treatment of narcolepsy/cataplexy. Narcolepsy is a debilitating disorder characterized by an inability to properly maintain wakefulness, sleep attacks, a sudden loss of muscle function, and sleep paralysis. Narcolepsy is a non-progressive, life-long condition, which is estimated to affect 1/1,000 ~ 1/2,000 individuals (200,000 Americans) and is often under-diagnosed or mistaken for depression, epilepsy or medication side effects. Current available treatments for narcolepsy are palliative, symptom-oriented pharmacotherapies. Thus, not only are they ineffective for correcting the underlying neurochemical deficits, but they also exhibit various undesirable side-effects. Accumulating evidence indicates that the hypothalamic neuropeptides, termed orexins (also hypocretins), play an important role in sleep/wake control and that narcolepsy is an orexin-deficiency syndrome. Transgenic mouse strains that have been engineered to closely mimic the neurochemical situation in human narcoleptics, i.e. with a postnatal loss of orexin neurons, exhibit all symptoms of narcolepsy/cataplexy and can be cured by providing exogenous orexin. However, orexins are peptides, thus orally inactive and blood-brain barrier impermeable, and cannot be used as a therapeutic agent. Using high throughput screening, we have identified the first orexin receptor-specific small molecule agonists. We propose a medicinal chemistry program to improve their potency and pharmacokinetic properties to provide brain penetrable pre-clinical candidates for use in proof-of-concept studies in a transgenic animal model of human narcolepsy. A unique multidisciplinary team with biological, chemical, and pharmacological expertise has been assembled to tackle this problem via a multi-pronged approach. Synthetic chemistry will be deployed for the iterative synthesis and optimization of small molecule orexin agonists, studies which will be guided by a comprehensive in vitro evaluation of potency and selectivity, and pharmacological assessment for drug-like properties. Finally, selected candidates will be evaluated in in vivo animal models of human narcolepsy. Our team is ideally suited to achieve the above stated overall goal. The discovery of orexins, and their role in sleep/wake cycles and narcolepsy, emanated from the laboratory of Dr. Yanagisawa, who also developed the transgenic animal models that fully recapitulate the human disease. Combining these strengths in orexin biology with synthetic chemistry and pharmacological expertise, there is a high likelihood that this team will provide the first small molecule preclinical candidates for orexin replacement therapy. We propose the development of drug-like preclinical candidates for the treatment of narcolepsy, a debilitating disorder that is estimated to affect approximately 200,000 Americans. Current available treatments for narcolepsy exhibit various undesirable side-effects and are ineffective for correcting the underlying neurochemical deficits. Our proposed research is highly relevant, as it seeks to translate the basic science finding that orexin deficiency is at the root of narcolepsy, into a drug candidate that is designed to replace endogenous orexin, and as such provide a potential cure for human narcolepsy.